Nicotine addiction is very common in the United States and is a major health concern. It is not yet known why some people have an increased susceptibility to become addicted to nicotine. Cigarette smoking is much more prevalent in both non-medicated and medicated patients with schizophrenia compared to the general population. The long-term goal of this research program is to examine factors contributing to this comorbidity, using a rodent model of schizophrenia. An animal model of schizophrenia that parallels the behavioral, neurochemical, and developmental aspects of schizophrenia is the neonatal ventral hippocampus lesion (NVHL) model. Some of the cognitive, negative, and positive symptoms of schizophrenia are observed in the NVHL model, including deficits in prepulse inhibition (PPI), an operational measure of sensory gating. Nicotine increases PPI in both humans and animals. PPI deficits have been observed in psychiatric as well as non-psychiatric subjects after abstaining from smoking. Therefore, an increased vulnerability to nicotine addiction may be related to deficits in PPI. The proposed studies will determine whether nicotine can improve disrupted PPI in the NVHL animal model of schizophrenia, analogous to the effects of cigarette smoking in human patients with schizophrenia. These studies will also determine whether NVHL rats exhibit an increased preference for nicotine compared to controls. Additional studies will assess the effect of bupropion, an antidepressant that is prescribed for smoking cessation, on PPI deficits and nicotine preference in the NVHL model of schizophrenia. Since heavy smoking is a common occurrence in patients with schizophrenia, a better understanding of the effect of nicotine in schizophrenic-like animal models may lead to the identification of neurobiological factors that influence the vulnerability to become addicted to nicotine and lead to the development of novel pharmacological approaches for smoking cessation and/or the treatment of schizophrenia.